Many cytokines are polypeptides which directly or indirectly mediate host defense mechanisms and/or which mediate tissue growth differentiation. Cytokines have been recognized which mediate host defense against cancer and/or infection. Such cytokines include the interferons (IFN-.alpha., IFN-.beta. and IFN-.gamma.), tumor necrosis factor (TNF-.alpha.), lymphotoxin (TNF-.beta.), the interleukins (IL1, 2, 3, 4, 5 and 6), leukoregulin, natural killer cell cytotoxic factor (NKCF), transforming growth factor (TGF), colony stimulating factors (CSF) such as macrophage (M-CSF), granulocyte (G-CSF) and macrophage, granulocyte-CSF (G,M-CSF) and oncostatin M. Each of the aforementioned cytokines have unique characteristics and a unique range of antiproliferative, cytostatic, antiviral or growth regulatory activity.
Several cytokines are synthesized by leukocytes, commonly in response to stimulation by microorganisms, antigens or mitogens. This has been observed in vitro. Following this stimulation in cell culture, the supernatant fluid is retrieved and cytokine activity identified, isolated and further characterized. In recent years, it has become increasingly clear that IL2 is not the only factor controlling T cell growth. Indeed, several cytokines, including IL4 (Fernandez-Botran et al., Proc. Natl. Acad. Sci. USA, 83; 9689-9693, 1986; Lichtman et al., Proc. Natl. Acad. Sci. USA, 84: 4293-4297, 1987), G,M-CSF (Woods et al., J. Immunol., 138: 4293-4297, 1987; Kupper et al., J. Immunol., 138, 4288-4292, 1987) and, in human system, the combination of IL1 and IL6 (Houssiau et al., Eur. J. Immunol. 18: 653-656, 1988), have now been shown to induce IL2-independent T cell proliferations. Consequently, the regulation of T cell growth is more complex than originally thought, although IL2 is a potent and broadly active T cell growth factor.
An important subset of T cells is the helper T cell (T.sub.H). At least two types of helper T cells have been identified on the basis of functional criteria. One type of T.sub.H cell (T.sub.H 1) helps B cells in a linked, antigen-specific manner, and is required early in the response. Another type of T.sub.H 2) helps B cells in a nonlinked manner and is required later in the response.
Several years ago, a collection of helper T cell lines from lymph nodes of antigen-primed mice was obtained using the procedure described by Corradin et al., J. Immunol., 119: 1048-1053, 1977. These cell lines were initiated by culture in the presence of antigen and were subsequently maintained, without addition of exogenous growth factors, by regular feeding with antigen and irradiated splenic antigen-presenting cells. Most of these cells produce large amounts of IL3, IL4, IL5 and IL6, but no IL2 and, therefore, belong to the T.sub.H 2 type defined by Mosmann et al., J. Immunol., 136: 2348-2357, 1986.
In accordance with the present invention, it is surprisingly discovered that two clones derived from the above-mentioned cell lines proliferated in response to their own conditioned medium in the absence of antigen and feeder cells. The subject invention relates to a novel T cell growth factor distinct from other known cytokines. The new growth factor is useful as a therapeutic compound to stimulate proliferation of helper T cells.